Psoriasis is a chronic skin disease characterized by erythematous plaques of thickened, reddening, and scaling skin. Psoriasis affects about 2% of the population. Onset occurs most often in early adult life, but also may begin in childhood or in aged people. Severity of the disease varies and is usually characterized by alternating periods of remission and flare-up. In more serious cases, psoriasis can affect up to 90% of the skin and can be life threatening
At the cellular level, psoriasis is characterized by a hyper proliferation of epidermal keratinocytes, accompanied by infiltration of T lymphocytes and other immune system cells, the latter giving rise to inflammation similar to that in autoimmnune diseases. The epidermal turnover time for a keratinocyte to travel from the basal cell layer to the stratum corneum normally is 14 days, during which the keratinocyte undergoes a complex series of changes in gene expression resulting in cell death--"terminal differentiation." In a psoriasis patient, the epidermal turnover time is 2 days, with marked increase in proliferation of keratinocytes, which are subsequently shed in a relative immature, or less differentiated, form.
Currently, there is no long-term cure for psoriasis. Treatments include coal tar preparations (natural coal tar or the distillate anthralin), topical corticosteroids, mechanical treatments to remove scale, and antimetabolites such as methotrexate. The photosensitizing drug, psoralen, combined with long wavelength ultraviolet light (PUVA), and synthetic retinoids also are used. While mild to moderate cases can be treated somewhat effectively, more extensive cases are difficult and tend to be resistant to either topical therapy or ultraviolet phototherapy. Moreover, systemic use of traditional antipsoriatic drugs, or prolonged use of topical steroids, can lead to undesirable side effects or rebound worsening of psoriasis.
Genetic analysis indicates that at least some forms of psoriasis include an inherited component, and intense efforts are underway to locate "psoriasis susceptibility genes." The similarity to autoimmune diseases, and the increased incidence of HLA-13, HLA-17, HLA-Cw6, and HLA-DRw7 in affected individuals has focused attention on on immunomodulatory strategies and the development of new drugs which decrease T-cell activation or deplete activated T-cell pools. Research has been severely impeded, however, by the lack of an animal model which reflects all the diverse clinical and cellular changes present in psoriatic plaques.
An alternative approach to immune modulation that may avoid potential side effects from drugs of this type is to focus on the abnormal keratinocyte differentiation in psoriasis. Keratinocyte maturation is associated with the production of proteinases, which can degrade the surrounding extracellular matrix to allow cell migration to the superficial layers and activate cells to divide, either directly, or indirectly by activating cytokines precursors. At terminal differentiation, the formation of a stable stratum corneum would require that the activity of such proteinases be down-regulated. Several proteinases, such as plasminogen activator and cathepsin B, have been shown to be present in normal skin, and it is possible that the cellular pathophysiology in psoriasis may result from excessive and unregulated levels of proteinases.
In psoriasis, abnormalities in the expression of both urokinase plasminogen activator (u-PA) and tissue plasminogen activator (t-PA) expression have been observed. The most dramatic change is the greatly enhanced t-PA expression in suprabasal epidermis. Jensen et al., J. Invest. Dermatol. 90(6):777-782 (1988). Baird et al., J. Invest. Dermatol. 95(5):548-552 (November 1990). Biopsies from 40 patients with psoriasis before and after topical (anthralin, corticosteroid) and systemic (PUVA) treatments by the autohistographic fibrin film method showed that both u-PA and t-PA immunoreactivity were present in psoriatic patches but absent from normal and treated, clear skin. Lotti et al., Int. J. Dermatol. 29(7):528-530 (1990). Moreover, increase in PAI-2 in psoriatic epidermis, in the same suprabasal areas as t-PA suggests that PAI-2 has a protective role in cutaneous pathologies that elicit abnormal wound healing patterns. Lyons-Giordano et al., "Expression of plasminogen activator inhibitor type 2 in normal and psoriatic epidermis," Histoclemistry 101(2):105-112 (February 1994).
It is apparent, therefore, that new methods and compositions for treating psoriasis are greatly to be desired. In particular, it would be desirable to develop new methods and compositions for treating psoriasis that regulate the plasminogen activator/inhibitor system and in particular that utilize plasminogen activator inhibitors.